Drosophila como modelo para identificar genes involucrados en neurodegeneración

MF CERIANI

4Buenos Aires, 23-25 Septiembre

Congreso; Simposio de Alternativas. Congreso de AACyTAL-FESSACAL. Buenos Aires, 23-25 Septiembre 2014.; 2014

AACyTAL-FESSACAL

Neurodegenerative diseases encompass a broad variety of motor and cognitive disorders that are accompanied by death of specific neuronal populations or brain regions. Over the last decade Drosophila has become a well-established model to study the cellular and molecular basis of neurodegenerative diseases. A number of years ago our laboratory undertook a misexpression screen to identify genes whose deregulation could render organisms more prone to develop neurodegeneration. The screen relied on the automated evaluation of locomotor behavior in young and aged flies, and looked for signs of premature and progressive loss of rhythmic activity as a proxy for deregulated genes potentially linked to neurodegeneration. One of the interesting candidates showing progressive arrhythmicity has reduced enabled (ena) levels. ena encodes a protein involved in cytoskeleton remodeling which plays a crucial role during the development of the nervous system. In the mutant, continuous ena down-regulation gave rise to progressive vacuolization in specific regions of the adult brain, increased apoptosis, as well as the abnormal staining of pre-synaptic markers, suggesting that axonal transport could partially account for the degeneration observed in the mutant. To extend our understanding on the mechanisms of ENA-triggered degeneration we then investigated the effect of silencing ena ortholog genes in mouse hippocampal neurons. We found that ENA/VASP down-regulation led to axonal retraction and concomitant neuronal cell death through an apoptotic pathway. Remarkably, reduction in ENA/VASP levels blocked the neuritogenic effect of a specific RhoA kinase (ROCK) inhibitor, suggesting that these proteins interact with the Rho-signaling pathway. These results underscore that ENA not only is required during the establishment of the embryonic nervous system but also to maintain the cellular homeostasis of the adult nervous system. Given the striking conservation at the cellular level between Drosophila and mice, progress in the fly model system will ultimately shed light on the pathways relevant to neurodegeneration in the mammalian brain.